The long term goal of this project is to address the problems introduced into the rational synthesis of complex organic molecules by stereochemistry, both relative and absolute. In the five-year program proposed, several types of studies will be carried out. The most fundamental will be physical organic investigations of lithium and magnesium enolates, important intermediates in organic synthesis. These studies will try to assess the importance of aggregation on reactivity, specifically on stereochemistry. Reseach directed toward the development of a protocol for catalytic, asymmetric aldol reactions using the readily-available boron enolates will also be carried out. The stereochemical personalities of two less-studied classes of reagents--magnesium enolates and metalloenamines--will be systematically investigated. The sterochemistry of the reactions of immonium ions and thionium ions with nucleophilic alkenes will be surveyed. A productive protocol for the stereoselective construction of conformationally-flexible molecules will be further developed. This strategy employs a highly stereoselective aldol reaction, coupled with further reactions that are known to transfer chirality with high selectivity. The specific sequence to be studied will utilize sequential aldol, Claisen, and Mislow/Evans rearrangement ot prepare building blocks having three stereocenters. The method will be appleid to the total synthesis of the natural porducts ACRL toxin IIIA and myxalamide. The use of chiral alpha-silyloxy ketones for asymmetric aldol constructions will be further developed and applied to the synthesis of the rifamycin S ansa chain. Finally, erythronolide A will be synthesized as a exercise in development of aldol strategy. The main theme of this research project is stereochemistry in synthesis, a topic of great relevance to modern medicinal chemistry.